Treatment of ocular inflammatory diseases using laquinimod

ABSTRACT

Disclosed is a method for treating an ocular inflammatory disease (OID), e.g., uveitis or conjunctivitis, comprising periodic administration of a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof. Also provided is a pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof for use in treating a subject suffering from an OID, uveitis, bacterial conjunctivitis, viral conjunctivitis, an inflammation of the orbital tissue, the lacrimal apparatus, the eyelid, the cornea, the retina or the optic pathway. This application also provides a method for treating a subject suffering from an autoimmune disease-associated ocular inflammation comprising periodic ocular administration to the subject a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt, and an ocular pharmaceutical composition comprising laquinimod or a pharmaceutically acceptable salt thereof for use in treating an autoimmune disease-associated ocular inflammation.

This application claims benefit of U.S. Provisional Application No.61/655,526, filed Jun. 5, 2012, the entire content of which is herebyincorporated by reference herein.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Ocular Inflammatory Disease (“OID”) is a general term for describinginflammation affecting one or more parts of the eye or surrounding eyetissue. Uveitis is the inflammation of the uvea or the uveal tract,which includes the iris, the ciliary body and the choroid portions ofthe eye. Inflammation of the overlying retina, called retinitis, or ofthe optic nerve, called optic neuritis, may occur with or withoutaccompanying uveitis. Anatomically, uveitis may be classified asanterior, intermediate, posterior or diffuse, depending on the portionof the uveal tract that is affected. Anterior uveitis is localizedprimarily to the anterior segment of the eye and includes iritis andiridocyclitis. Intermediate uveitis, also called peripheral uveitis, iscentered in the area immediately behind the iris and lens in the regionof the ciliary body and pars plana, hence the alternate terms “cyclitis’and “pars planitis.” Posterior uveitis signifies any of a number offorms of retinitis, choroiditis, or optic neuritis. Diffuse uveitisimplies inflammation involving all parts of the eye, including anterior,intermediate, and posterior structures (The Merck Manual, 1999).

Inflammation from uveitis may result in a variety of other eyeconditions, including glaucoma, cataracts, and cystoid macular edema,and ultimately may lead to permanent vision loss. Uveitis is the thirdleading cause of blindness in the developed world. There is no one rootcause of uveitis or other OID. Causes range from infections by certainbacteria, parasites, fungus, and viruses; trauma; autoimmune disease;inducement by certain drugs such as bisphosphonates or sulfaonamides;and inducement by certain malignant cancers such as lymphoma.

Conjunctivitis is another OID that causes inflammation of theconjunctival tissue. The conjunctiva is the thin, transparent layer oftissue that covers the outside surface of the eye, including the corneaand the visible sclera (the white part of the eye), and also lines theeyelids. The conjunctiva secretes oils and mucus and is responsible formoistening and lubricating the eye. There are several types ofconjunctivitis, some more severe than others. Seasonal and perennialallergic conjunctivitis (SAC and PAC) are generally associated withallergic reactions. The more severe vernal and atopickeratoconjunctivitis (VKC and AKC) are also associated withhypersensitivity to an allergen, but inflammation occurs in both theconjunctiva and the cornea. VKC is intermittent and often occursseasonally, most commonly in summer, while AKC does not have a seasonalcomponent. Symptoms of SAC and PAC include itching, swelling and tearingwhile symptoms for VKC and AKC are more severe and include pain, visualloss and corneal scarring.

Generally, allergic eye reactions such as that caused by OID consist oftwo different phase reactions, early-phase reaction and late phasereaction, and each reaction has different cell types considered to bethe major effector cells for production of the eye disease. Early-phasereaction, which occurs with SAC and PAC, for example, involves mastcells as the major effector cells, while late-phase reaction, whichoccurs with VKC and AKC, for example, involves eosinophils as the majoreffector cells.

Current therapies for allergic conjunctivitis include anti-allergicswith antihistamine and mast cell stabilizing functions for treatment ofSAC, steroids for PAC, and steroids and/or cyclosporine A for AKC andVKC. There is a need for additional treatment of OID.

SUMMARY OF THE INVENTION

Disclosed is a method of treating ocular inflammatory disease (OID),including uveitis and conjunctivitis, using laquinimod or apharmaceutically acceptable salt thereof. Laquinimod is a novelsynthetic compound with high oral bioavailability, which has beensuggested as an oral formulation for Relapsing Remitting MultipleSclerosis (RRMS). Laquinimod and its sodium salt form are described, forexample, in U.S. Pat. No. 6,077,851.

This application provides a method of treating a subject suffering froman ocular inflammatory disease (OID), the method comprising periodicadministration to the subject of a therapeutically effective amount oflaquinimod or a pharmaceutically acceptable salt thereof effective totreat the subject.

This application also provides a pharmaceutical composition comprisinglaquinimod or a pharmaceutically acceptable salt thereof for use intreating a subject suffering from an ocular inflammatory disease.

This application also provides a pharmaceutical composition comprisinglaquinimod or a pharmaceutically acceptable salt thereof for use intreating a subject suffering from uveitis, bacterial conjunctivitis,viral conjunctivitis, or an inflammation of the orbital tissue, thelacrimal apparatus, the eyelid, the cornea, the retina or the opticpathway.

This application also provides a pharmaceutical composition for use intreating a subject suffering from allergic conjunctivitis or uveitiscomprising a unit dose of 10 μL of an aqueous pharmaceutical solutionwhich contains in solution at least 0.2 mg laquinimod or apharmaceutically acceptable salt thereof.

This application also provides a method of treating a subject sufferingfrom an autoimmune disease-associated ocular inflammation, the methodcomprising periodic ocular administration to the subject atherapeutically effective amount of laquinimod or a pharmaceuticallyacceptable salt thereof effective to treat the subject.

This application also provides an ocular pharmaceutical compositioncomprising laquinimod or a pharmaceutically acceptable salt thereof foruse in treating an autoimmune disease-associated ocular inflammation.

DETAILED DESCRIPTION OF THE INVENTION

This application provides for a method of treating a subject sufferingfrom an ocular inflammatory disease (OID), the method comprisingperiodic administration to the subject of a therapeutically effectiveamount of laquinimod or a pharmaceutically acceptable salt thereofeffective to treat the subject.

In one embodiment, the ocular inflammatory disease is uveitis, bacterialconjunctivitis, viral conjunctivitis, or an inflammation of the orbitaltissue, the lacrimal apparatus, the eyelid, the cornea, the retina orthe optic pathway. In an embodiment, the OID is conjunctivitis. Inanother embodiment, the conjunctivitis is bacterial conjunctivitis. Inyet another embodiment, the conjunctivitis is viral conjunctivitis.

In one embodiment, the OID is uveitis. In another embodiment, theuveitis is anterior uveitis. In another embodiment, the uveitis isintermediate uveitis. In another embodiment, the uveitis is posterioruveitis. In yet another embodiment, the uveitis is diffuse uveitis.

In one embodiment, the therapeutically effective amount of laquinimod apharmaceutically acceptable salt thereof is effective to reduce asymptom of the ocular inflammatory disease in the subject, induceclinical response, induce or maintain clinical remission, inhibitdisease progression, inhibit a disease complication, reduce intraocularinflammation or reduce retina tissue destruction in the subject. Inanother embodiment, the therapeutically effective amount of laquinimodor pharmaceutically acceptable salt thereof is effective to reduce oneor more symptoms of the OID in the subject. In another embodiment, thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is effective to reverse the progression of theOID. In another embodiment, the therapeutically effective amount oflaquinimod or pharmaceutically acceptable salt thereof is effective toinduce a clinical response or induce or maintain clinical remission inthe subject suffering from the OID. In another embodiment, thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is effective to inhibit disease progression ordisease complication in the subject suffering from the OID. In anotherembodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to decreaseeosinophil infiltration at the site of inflammation. In anotherembodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduceintraocular inflammation. In yet another embodiment, the therapeuticallyeffective amount of laquinimod or pharmaceutically acceptable saltthereof is effective to reduce retina tissue destruction in the subject.

In one embodiment of the present invention, the OID is conjunctivitisand the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduce asymptom of conjunctivitis in the subject. In another embodiment of thepresent invention, the OID is uveitis and the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof iseffective to reduce a symptom of uveitis in the subject. In yet anotherembodiment of the present invention, the ocular inflammatory disease isan inflammation of the orbital tissue, the lacrimal apparatus, theeyelid, the cornea, the retina or the optic pathway and thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is effective to reduce a symptom of theinflammation in the subject.

In one embodiment, the laquinimod or pharmaceutically acceptable saltthereof is administered topically. In another embodiment, administrationof the laquinimod or pharmaceutically acceptable salt thereof is ocularadministration. In another embodiment, administration of the laquinimodor pharmaceutically acceptable salt thereof is oral administration. Inanother embodiment the periodic administration is local administration.In another embodiment, the laquinimod or pharmaceutically acceptablesalt thereof is administered to the affected eye of the subject.

In one embodiment, the laquinimod or pharmaceutically acceptable saltthereof is administered in the form of a liquid or a gel. In anotherembodiment, the laquinimod or pharmaceutically acceptable salt thereofis administered in liquid form. In another embodiment, the laquinimod orpharmaceutically acceptable salt thereof is administered in a liquid eyedrop. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered in gel form.

In one embodiment, the concentration of laquinimod or pharmaceuticallyacceptable salt thereof in the liquid or gel is 0.5% (5 mg/ml)-10.0%(100 mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is 1.0% (10 mg/ml)-7.0% (70mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is 1.0% (10 mg/ml)-5.0% (50mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is about 1.0% (10 mg/ml). Inanother embodiment, the concentration of laquinimod or pharmaceuticallyacceptable salt thereof is about 5.0% (50 mg/ml). In an embodiment, thevolume of liquid or gel per administration is about 10 μl. As usedherein “mg/ml” designates the amount (mg) of laquinimod orpharmaceutically acceptable salt thereof per volume (ml) of solution.

In another embodiment, the therapeutically effective amount oflaquinimod or pharmaceutically acceptable salt thereof is 0.05-4.0 mgper administration. In another embodiment, the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof is0.05-2.0 mg per administration. In another embodiment, thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is about 0.1 mg per administration. In anotherembodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is about 0.5 mg peradministration. In yet another embodiment, the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof is atleast 0.02 mg/day.

In an embodiment, the periodic administration is 1-5 times a day. In oneembodiment, the periodic administration is once a day. In anotherembodiment, the periodic administration is twice a day. In anotherembodiment, the periodic administration is three times a day. In yetanother embodiment, the periodic administration is once every 2 days.

In an embodiment of the invention, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 2 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 5 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 10 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for about 7 days.

In an embodiment of the present invention, the ocular inflammatorydisease is uveitis and the therapeutically effective amount oflaquinimod or pharmaceutically acceptable salt thereof is at least 0.2mg/day.

In another embodiment of the present invention, the ocular inflammatorydisease is allergic conjunctivitis and the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof is atleast 0.2 mg/day. In another embodiment, the OID is seasonal allergicconjunctivitis (SAC) or perennial allergic conjunctivitis (PAC). Inanother embodiment, the OID is atopic keratoconjunctivitis (AKC) orvernal keratoconjunctivitis (VKC).

In one embodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduce asymptom of the conjunctivitis in the subject. In another embodiment, thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is effective to inhibit late ocular anaphylaxisin the subject. In another embodiment, the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof iseffective to reduce eosinophil infiltration in to the conjunctiva of thesubject. In yet another embodiment, the eosinophil infiltration into theconjunctiva is measured by eosinophil density in the conjunctiva.

In one embodiment, the eosinophil density is reduced by at least 40% ascompared to a subject not administered laquinimod or pharmaceuticallyacceptable salt thereof. In another embodiment, the eosinophil densityis reduced by at least 45% as compared to a subject not administeredlaquinimod or pharmaceutically acceptable salt thereof. In anotherembodiment, the eosinophil density is reduced by at least 50% ascompared to a subject not administered laquinimod or pharmaceuticallyacceptable salt thereof. In another embodiment, the eosinophil densityis reduced by at least 55% as compared to a subject not administeredlaquinimod or pharmaceutically acceptable salt thereof. In anotherembodiment, the eosinophil density is reduced by at least 60% ascompared to a subject not administered laquinimod or pharmaceuticallyacceptable salt thereof. In yet another embodiment, the eosinophildensity is reduced by at least 65% as compared to a subject notadministered laquinimod or pharmaceutically acceptable salt thereof.

In one embodiment, the laquinimod or pharmaceutically acceptable saltthereof is administered topically. In another embodiment, administrationof the laquinimod or pharmaceutically acceptable salt thereof is ocularadministration. In another embodiment, administration of the laquinimodor pharmaceutically acceptable salt thereof is oral administration. Inanother embodiment the periodic administration is local administration.In another embodiment, the laquinimod or pharmaceutically acceptablesalt thereof is administered to the affected eye of the subject.

In one embodiment, the laquinimod or pharmaceutically acceptable saltthereof is administered in the form of a liquid or a gel. In anotherembodiment, the laquinimod or pharmaceutically acceptable salt thereofis administered in liquid form. In another embodiment, the laquinimod orpharmaceutically acceptable salt thereof is administered in a liquid eyedrop. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered in gel form.

In one embodiment, the concentration of laquinimod or pharmaceuticallyacceptable salt thereof in the liquid or gel is 2.0% (20 mg/ml)-10.0%(100 mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is 2.0% (20 mg/ml)-7.0% (70mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is 2.0% (20 mg/ml)-5.0% (50mg/ml). In another embodiment, the concentration of laquinimod orpharmaceutically acceptable salt thereof is about 5.0% (50 mg/ml). In anembodiment, the volume of liquid or gel per administration is about 10μl. As used herein “mg/ml” designates the amount (mg) of laquinimod orpharmaceutically acceptable salt thereof per volume (ml) of solution.

In one embodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is 0.2-4.0 mg peradministration. In another embodiment, the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof is0.2-2.0 mg per administration. In yet another embodiment, thetherapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is about 0.5 mg per administration.

In an embodiment, the periodic administration is 1-5 times a day. In oneembodiment, the periodic administration is once a day. In anotherembodiment, the periodic administration is twice a day. In anotherembodiment, the periodic administration is three times a day. In yetanother embodiment, the periodic administration is once every 2 days.

In an embodiment of the invention, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 2 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 5 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for a period of 10 to14 days. In another embodiment, the laquinimod or pharmaceuticallyacceptable salt thereof is administered once daily for about 7 days.

In one embodiment, the laquinimod or pharmaceutically acceptable saltthereof is in a pharmaceutical composition which comprises apharmaceutically acceptable carrier. In another embodiment, thepharmaceutical composition is in the form of a tablet or capsule. Inanother embodiment, the pharmaceutical composition is a liquid solution.In another embodiment, the liquid solution is prepared by dissolvinglaquinimod or a pharmaceutically acceptable salt thereof in a sterilepH-neutral solution. In one embodiment, the pH-neutral solution issaline. In another embodiment, the pH-neutral solution is phosphatebuffered saline (PBS). In another embodiment, the pH-neutral solution issterile water.

In one embodiment, the pharmaceutical composition is a gel. In anotherembodiment, the pharmaceutically acceptable carrier is hydrophilic. Inanother embodiment, the pharmaceutically acceptable carrier comprises atleast one gelling or suspension agent. Examples of suitable gelling orsuspension agents known in the art include carbomers, modified cellulosederivatives, naturally-occurring, synthetic or semi-synthetic gums suchas xanthan gum, acacia and tragacanth, modified starches, co-polymerssuch as those formed between maleic anhydride and methyl vinyl ether,colloidal silica and methacrylate derivatives sold under the trade nameEUDRAGIT® (available from Evonik Industries, Essen, Germany) or amixture thereof. In another embodiment, the pharmaceutically acceptablecarrier comprises at least one surfactant or emulsifying agentcompatible with any pharmacologically active agents or pharmaceuticallyacceptable components present. In one embodiment, the surfactantsinclude non-ionic, cationic and anionic surfactants. In anotherembodiment, the surfactants include non-ionic surfactants such assorbitan fatty acid esters (SPANS®) and the correspondingpolyoxyethylene (POE) adducts (TWEENS®).

In an embodiment, the pharmaceutically acceptable salt of laquinimodincludes lithium, sodium, potassium, magnesium, calcium, manganese,copper, zinc, aluminum and iron. Salt formulations of laquinimod and theprocess for preparing the same are described in, e.g., U.S. PatentApplication Publication No. 2005/0192315 and PCT InternationalApplication Publication No. WO 2005/074899, each of which is herebyincorporated by reference into this application. In one embodiment, thepharmaceutically acceptable salt of laquinimod is laquinimod sodium.

In an embodiment of the invention, the method comprises topicallyadministering to the affected eye of the subject a 5.0% (50 mg/ml)solution of laquinimod sodium once per day for a period of 14 days. Inanother embodiment, the method comprises topically administering to theaffected eye of the subject a 5.0% (50 mg/ml) solution of laquinimodsodium once per day for a period of 10 days.

In an embodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is 1.0-1.5 mg/day. In anotherembodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is 1.2 mg/day. In anotherembodiment, the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is at least 0.2 mg/day.

In an embodiment of the invention, the subject is human.

This application also provides for a pharmaceutical compositioncomprising laquinimod or a pharmaceutically acceptable salt thereof foruse in treating a subject suffering from an ocular inflammatory disease.

This application also provides for a pharmaceutical compositioncomprising laquinimod or a pharmaceutically acceptable salt thereof foruse in treating a subject suffering from uveitis, bacterialconjunctivitis, viral conjunctivitis, or an inflammation of the orbitaltissue, the lacrimal apparatus, the eyelid, the cornea, the retina orthe optic pathway.

This application also provides for a pharmaceutical composition for usein treating a subject suffering from allergic conjunctivitis or uveitiscomprising a unit dose of 10 μL of an aqueous pharmaceutical solutionwhich contains in solution at least 0.2 mg laquinimod or apharmaceutically acceptable salt thereof. In an embodiment, thepharmaceutical composition is an ocular pharmaceutical composition.

This application also provides for a pharmaceutical compositioncomprising a therapeutically effective amount of laquinimod or apharmaceutically acceptable salt thereof for use in treating a subjectsuffering from uveitis, bacterial conjunctivitis, viral conjunctivitis,or an inflammation of the orbital tissue, the lacrimal apparatus, theeyelid, the cornea, the retina or the optic pathway. In an embodiment,the pharmaceutical composition is an ocular pharmaceutical composition.

This application provides for a method of reducing eosinophil density inthe conjunctival tissue of a subject comprising periodicallyadministering to the subject an amount of laquinimod or apharmaceutically acceptable salt thereof effective to reduce theeosinophil density in the conjunctival tissue of the subject. Thisapplication also provides for a method of reducing intraocularinflammation in a subject comprising periodically administering to thesubject an amount of laquinimod or a pharmaceutically acceptable saltthereof effective to reduce intraocular inflammation in the subject.This application also provides for a method of reducing retina tissuedestruction in a subject comprising periodically administering to thesubject an amount of laquinimod or a pharmaceutically acceptable saltthereof effective to reduce retina tissue destruction in the subject. Inan embodiment, the amount of laquinimod or pharmaceutically acceptablesalt thereof is a therapeutically effective amount. In anotherembodiment, the administration is ocular administration.

This application also provides for a pharmaceutical compositioncomprising laquinimod or a pharmaceutically acceptable salt thereof foruse in reducing eosinophil density in the conjunctival tissue of asubject or for reducing intraocular inflammation or destruction ofretina tissue in a subject. In an embodiment, the pharmaceuticalcomposition comprises a therapeutically effective amount of laquinimodof a pharmaceutically acceptable salt thereof. In another embodiment,the pharmaceutical composition is an ocular pharmaceutical composition.

This application also provides a method of treating a subject sufferingfrom an autoimmune disease-associated ocular inflammation, the methodcomprising periodic ocular administration to the subject of atherapeutically effective amount of laquinimod or a pharmaceuticallyacceptable salt thereof effective to treat the subject.

This application also provides an ocular pharmaceutical compositioncomprising laquinimod or a pharmaceutically acceptable salt thereof foruse in treating an autoimmune disease-associated ocular inflammation.

All combinations of the various elements described herein are within thescope of the invention.

Definitions

“Ocular inflammatory diseases” or “OID” as used herein means theinflammation affecting one or more parts of the eye or surrounding eyetissue other than inflammation resulting from an autoimmune disease. OIDmay include, but is not limited to, inflammation of the orbital tissues,the lacrimal apparatus, the eyelid, the conjunctiva (conjunctivitis),the cornea, the retina, a component of the optic pathway, e.g., theoptic nerve, and a component of the uveal tract (uveitis), i.e., theiris, ciliary body and choroid. Specific examples of OID includeuveitis, acute conjunctivitis, viral conjunctivitis, nongonococcalbacterial conjunctivitis, adult gonococcal conjunctivitis, inclusionconjunctivitis, seasonal allergic conjunctivitis, chronicconjunctivitis, granular conjunctivitis, perennial allergicconjunctivitis, episcleritis, scleritis, atopic keratoconjunctivitis,and vernal keratoconjunctivitis.

Unlike the use of the term OID herein, the literature may use the termin a less definite manner to refer to ocular inflammation generally, andoften including ocular inflammation secondary to an underlying systemicinflammatory disease different from inflammation which representslocalized pathologic process without systemic involvement (Gordon, 2006;Rothova et al., 1992; Optometric Clinical Practice Guideline, 2002.) Forexample, conjunctivitis may result from primary involvement of theconjunctival tissue or may occur secondary to other systemic conditionsthat produce conjunctival inflammation (Optometric Clinical PracticeGuideline, 2002.) In one study conducted by Rothova et al., systemicdisease which could be considered to be causally related to ocularinflammation was diagnosed in 26% of the 865 uveitis patients observed(Rothova et al.). However, as used herein OID specifically excludesocular inflammation which results from an underying, systemic,autoimmune disease.

As used herein “autoimmune disease-associated ocular inflammation” isthe inflammation affecting one or more parts of the eye or surroundingeye tissue secondary to an autoimmune disease, and is specificallyexcluded from the definition of OID herein.

Autoimmune diseases contemplated by the present invention include eithercell-mediated disease (e.g., T-cell) or antibody mediated (e.g., B-cell)disorders. Such disorders can be inter alia arthritic conditions,demyelinating diseases and inflammatory diseases. For Example,autoimmune diseases contemplated herein include multiple sclerosis,autoimmune hemolytic anemia, autoimmune oophoritis, autoimmunethyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immunethrombocytopenic purpura, colitis, contact sensitivity disease, diabetesmellitus, Grave's disease, Guillain-Barre's syndrome, Hashimoto'sdisease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigusvulgaris, rheumatoid arthritis, and systemic lupus erythematosus.

“Administering to the subject” means the giving of, dispensing of, orapplication of medicines, drugs, or remedies to a subject to relieve,cure, or reduce the symptoms associated with a condition, e.g., apathological condition. The route of administration can be, e.g.,topical. Routes of administration can also be classified by whether theeffect is local (e.g., in topical administration) or systemic (e.g., inenteral or parenteral administration). “Local administration” as usedherein shall mean administration of a compound or composition directlyto where its action is desired, and specifically excludes systemicadministration. “Topical administration” of a compound or composition asused herein shall mean application of the compound or composition tobody surfaces such as the skin or mucous membranes such as eyes. “Ocularadministration” as used herein shall mean application of a compound orcomposition to the eye of a subject or to the skin around the eye(periocular skin) of a subject, i.e., local administration. Examples ofocular administration include topical administration directly to theeye, topical application to the eye lid or injection into a portion ofthe eye or eye socket. In addition, an “ocular pharmaceuticalcomposition” as used herein means a pharmaceutical compositionformulated for ocular administration.

An “amount” or “dose” of laquinimod as measured in milligrams refers tothe milligrams of laquinimod acid present in a preparation, regardlessof the form of the preparation.

“Unit dose” as used herein is the amount of a compound or composition tobe administered to the subject in a single administration. The unit dosedisclosed herein can be administered once daily, twice daily, threetimes daily, four times daily, five times daily, every other day,weekly, twice weekly, three times weekly, four times weekly, five timesweekly or six times weekly.

“About” in the context of a numerical value or range means ±10% of thenumerical value or range recited or claimed.

As used herein, “treating” encompasses, e.g., inducing inhibition,regression, or stasis of a disease, disorder or condition, orameliorating or alleviating a symptom of a disease, disorder orcondition. “Ameliorating” or “alleviating” a condition or state as usedherein shall mean to relieve or lessen the symptoms of that condition orstate. “Inhibition” of disease progression or disease complication in asubject as used herein means preventing or reducing the diseaseprogression and/or disease complication in the subject.

As used herein, “effective” as in an amount effective to achieve an end,i.e., “therapeutically effective amount”, means the quantity of acomponent that is sufficient to yield an indicated therapeutic responsewithout undue adverse side effects (such as toxicity, irritation, orallergic response) commensurate with a reasonable benefit/risk ratiowhen used in the manner of this disclosure. For example, an amounteffective to reduce inflammation. The specific effective amount willvary with such factors as the particular condition being treated, thephysical condition of the patient, the type of mammal being treated, theduration of the treatment, the nature of concurrent therapy (if any),and the specific formulations employed and the structure of thecompounds or its derivatives.

A “salt” is salt of the instant compounds which have been modified bymaking acid or base salts of the compounds. The term “pharmaceuticallyacceptable salt” in this respect, refers to the relatively non-toxic,inorganic and organic acid or base addition salts of compounds of thepresent invention. A pharmaceutically acceptable salt of laquinimod asused in this application includes lithium, sodium, potassium, magnesium,calcium, manganese, copper, zinc, aluminum and iron. Salt formulationsof laquinimod and the process for preparing the same are described,e.g., in U.S. Pat. No. 7,589,208 and PCT International ApplicationPublication No. WO 2005/074899, which are hereby incorporated byreference into this application.

Laquinimod can be administered in admixture with suitable pharmaceuticaldiluents, extenders, excipients, or carriers (collectively referred toherein as a pharmaceutically acceptable carrier) suitably selected withrespect to the intended form of administration and as consistent withconventional pharmaceutical practices. The unit will be in a formsuitable for topical administration. Laquinimod can be administeredalone but is generally mixed with a pharmaceutically acceptable carrier.As used herein, “pharmaceutically acceptable carrier” refers to acarrier or excipient that is suitable for use with humans and/or animalswithout undue adverse side effects (such as toxicity, irritation, andallergic response) commensurate with a reasonable benefit/risk ratio. Itcan be a pharmaceutically acceptable solvent, suspending agent orvehicle, for delivering the instant compounds to the subject.

General techniques and compositions for making dosage forms useful inthe present invention are described in the following references: ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds). These references in their entireties are herebyincorporated by reference into this application.

It is understood that where a parameter range is provided, all integerswithin that range, including tenths thereof, are also provided by theinvention. For example, “5-10%” includes 5.0%, 5.1%, 5.2%, 5.3%, 5.4%etc. up to 10.0%.

Immunomodulatory agents have been suggested for treating certain ocularinflammatory diseases (Foster 2003; Mishra 2011; Shah 1992). However,not all immunomodulatory agents are appropriate for OID. For example,fingolimod (Gilenya® from Novartis AG), an immunomodulatory agent, isknown to pose a risk of macular edema in patients with a history ofuveitis. (Sergott, 2011) The effects of laquinimod on OID have not beenpreviously reported.

In addition, in accordance with the present invention, a therapeuticallyeffective amount of laquinimod or a pharmaceutically acceptable saltthereof is delivered to a subject via ocular administration. Asdiscussed in Example 2 to follow, not all amounts of laquinimod or apharmaceutically acceptable salt thereof are “therapeutically effectiveamounts”. A therapeutically effective amount or means for determining atherapeutically effective amount for ocular/local administration oflaquinimod have not been previously reported.

This invention will be better understood by reference to theExperimental Examples which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL EXAMPLES Example 1: Evaluation of Efficacy Following DailyTopical Administration of Laquinimod in S-Antigen-Induced ExperimentalAutoimmune Uveitis in Rats (EAU Model) General.

A 1% (10 mg/ml) and a 5% (50 mg/ml) solution of laquinimod sodium wereprepared in sterile water. Dissolution of laquinimod powder was achievedby shaking, stirring, or low-speed vortex. The solutions were stored forup to 2 weeks at 2-8° C. and up to 24 hours at room temperature.Laquinimod solutions were prepared under light protection and wereprotected from light for the duration of the experiment. Cyclosporine Awas used as a reference material at a concentration of 25 mg/kg/j(Fluka). One 100 mg/4 ml in olive oil dose was prepared every 2 days andstored at room temperature.

Animals and Animal Husbandry.

Thirty two (32) female albino Lewis rats, approximately 8 weeks old,were used for this study. All rats were held in observation for at least3 days to monitor for signs of ill health or ocular abnormalities. Onlyhealthy animals were accepted for use in this study. The rats werehoused under identical environmental conditions, with a relativehumidity of 55%±10%, continuous ventilation, and an automatic hourlight/dark cycle. Environmental conditions were continuously controlledand recorded. Animals had free access to food and water.

Materials and Methods.

Thirty two female albino Lewis rats were randomly divided into four (4)groups of eight (8) rats. Ocular inflammation was induced at Day 1 byinjection of 100 μl of human S-antigen (100 μg) in Freud's completeadjuvant (4 mg/ml) into the footpad of each rat, and an intraperitonealinjection of 1 μg/100 μl pertussis toxin. Disease onset was typicallyobserved between Days 9 and 12 after immunization, and the disease statepeaked around Days 16 to 18. The study was halted when at least 60% ofthe vehicle group showed signs of inflammation.

Beginning on Day 7 until the end of the study, each animal group wastreated with a test solution in both eyes as shown in Table 1:

TABLE 1 Group Treatment Frequency 1 1% Laquinimod Once Daily (10 μl) 25% Laquinimod Once Daily (10 μl) 3 Vehicle Once Daily (10 μl) 4Cyclosporine A (25 mg/kg) Once Daily per os (1 ml/kg)

Both eyes of each rat were examined with a slit-lamp at baseline andthen every 2 days from Day 10 to the end of the study. Fifteen minutesprior to each examination, 10 μl of Mydriaticum (0.5% tropicamide) wasinstilled for papillary dilatation.

Immediately after euthanasia (i.e., at Day 16), both eyeballs of allrats of each group were enucleated and prepared for histologicalexamination. They were fixed in Bouin-Hollande solution, dehydrated, andembedded in paraffin wax. They were then cut into eight sections,approximate five to seven micrometers thick and stained with Trichome ofMasson. The retinal thickness and cell infiltration were evaluated andscored using the scale shown in Table 2:

TABLE 2 No tissue destruction and with any features in a score from 1-7,0 limited to total destruction of the various layers of the retinaSlight cellular infiltration without destruction of retina 1 Destructionof the outer segments of rods and cones 2 Destruction of the outernuclear layer 3-4 Destruction of the inner nuclear layer 5-6 Destructionof the ganglion layer 7

Results. Animal Body Weight.

Animal body weight was measured and recorded before induction andtreatment then at the end of the study. At baseline (treatment), meanbody weight per group was between 198 and 202 grams, with a standarddeviation of between ±5 grams and 11 grams. At the end of the study (Day16), mean body weight per group was between 202 grams and 209 grams,with a standard deviation of ±9 grams. There were no relevantdifferences in body weight between test material, vehicle, and referenceanimal group.

Ocular Evaluation.

The effect of test material and reference material on ocularinflammation was measured with slit lamp evaluation and scored using theclinical scoring as shown in Table 3:

TABLE 3 No sign of inflammation, normal iris dilatation afterinstillation with a 0 mydriatic drug Discrete inflammation in iris andconjunctiva 1 Dilatation of iris and conjunctival vessels 2 Hyperhemiain iris associated with the Tyndall effect in anterior 3 chamber Samesignas as score 3, but add 1 point each if syncehcia, fibrin, or 4-6hypopion (cell deposit in the inferior anterior chamber) were observed

In EAU rats, laquinimod showed a therapeutic effect on ocularinflammation. The 1% laquinimod solution administered once per dayreduced intraocular inflammation compared with the vehicle group. Themean clinical score at Day 16 was 1.3±2.1, compared with the vehiclegroup which was 4.8±1.3. The 5% laquinimod solution administered onceper day significantly reduced intraocular inflammation compared with thevehicle group. The mean clinical score at Day 16 was 0.6±1.5 comparedwith the vehicle group, which was 4.8±1.3. Six out of eight of the ratstested demonstrated no intraocular inflammation. As expected,cyclosporine A, the reference material, administered once per day at 25mg/kg, demonstrated complete inhibition of intraocular inflammation,with a mean clinical score at Day 16 of 0.0±0.0. Data for the slit lamptest is summarized in Table 4.

Histological examination of the eyeballs revealed that 1% laquinimodadministered once per day suppressed uveitis. The mean histologic gradeusing the scale set forth in paragraph above was 1.2±2.2 versus 5.8±2.3for the vehicle group. Only four eyes out of sixteen showed asignificant destruction of the retina associated with infiltration ofinflammatory cells. The 5% laquinimod administered once per daysignificantly reduced posterior uveitis as assessed by histologicalgrading. The mean histologic grade for this group was 0.7±1.9. Only twoeyes (from two different animals) out of sixteen showed a destruction ofthe retina associated with infiltration of inflammatory cells. Asexpected, the mean histologic grade for cyclosporine A (25 mg/kg) onceper day was 0.0±0.0, thereby totally protecting the retina fromdestruction. Summary data from the histological evaluation is shown inTable 5.

The 1% and 5% laquinimod solutions reduced the clinical signs of ocularinflammation. The reduced EAU clinical scores correlated well with thedecrease in the retinal damage and immune cell infiltration as assessedby histology.

TABLE 4 Slit Lamp Ocular Evaluation of Both Eyes in Albino Rats. Base-Day Day Day Day Treatment line 10 12 14 16 1% Laquinimod Mean 0.0 0.10.1 0.8 1.3 SD 0.0 0.3 0.3 1.8 2.1 Incidence % 0.0 6.3 6.3 18.8 31.3 5%Laquinimod Mean 0.0 0.0 0.0 0.3 0.6 SD 0.0 0.0 0.0 1.3 1.5 Incidence %0.0 0.0 0.0 6.3 12.5 Vehicle Mean 0.0 0.1 0.3 2.4 4.8 (sterile water) SD0.0 0.5 1.0 2.3 1.3 Incidence % 0.0 6.3 6.3 56.3 93.8 Cyclosporine AMean 0.0 0.0 0.0 0.0 0.0 (25 mg/kg/day) SD 0.0 0.0 0.0 0.0 0.0 per osIncidence % 0.0 0.0 0.0 0.0 0.0

TABLE 5 Histological Ocular Evaluation of Both Eyes in Albino Rats.Treatment Day 16 1% Laquinimod Mean 1.2 SD 2.2 5% Laquinimod Mean 0.7 SD1.9 Vehicle (sterile water) Mean 5.8 SD 2.3 Cyclosporine A (25mg/kg/day) Mean 0.0 per os SD 0.0

Example 2: Evaluation of Ocular Active Anaphylaxis Reduction FollowingTopical Ocular Administration of Laquinimod in Mice (Late Phase) UsingOvalbumin Model General.

Laquinimod solutions were prepared as in Example 1.

Animals and Animal Husbandry.

Forty (40) male Balb/c albino mice were used for this experiment. Themice were about 7-8 weeks old upon ordering, and were held inobservation for at least three (3) days to monitor for signs of illhealth or ocular abnormalities. Only healthy animals were accepted foruse in this study. The rats were housed under identical environmentalconditions, with a relative humidity of 55%±10%, continuous ventilation,and an automatic 12 hour light/dark cycle. Environmental conditions werecontinuously controlled and recorded. Animals had free access to foodand water.

Materials and Methods.

Forty (40) Balb/c albino mice were randomly allocated to five groups ofeight animals each. Only the right eyes of each animal were used in thisstudy. Animals were grouped as shown in Table 6:

TABLE 6 Group Treatment Sensitize/Challenge 1 Vehicle (sterile water) No2 Vehicle (sterile water) Yes 3 1% Laquinimod Yes 4 5% Laquinimod Yes 51% Prednisolone Yes

Sensitization.

On Days 1 and 8, animals in groups 2-5 were injected onceintraperitoneally with 0.2 ml of a mixture comprising 5 μg/ml ovalbuminand 15 mg/ml alum in phosphate buffered saline (PBS; pH 7.3-7.4).Animals of group 1 received a mock sensitization comprising 0.2 mlintraperitoneal injection of PBS only on Days 1 and 8.

Treatment Regimen.

Laquinimod or controls were delivered into the right conjunctival sac asfollows:

-   -   From Day 8 to Day 17, animals were dosed four times daily with        10 μl of either 1% laquinimod, 5% laquinimod, or vehicle.        Reference Group 5 was dosed with the same regimen, but starting        on Day 15. (**Note: Due to a technical error, four mice from        Group 1 (negative vehicle) were not dosed on Day 8 and one mouse        from Group 1 (negative vehicle) was not dosed on Day 11. This        was deemed not to be a critical error that would affect the        outcome of the study so the study was continued).    -   On Day 18, animals were dosed five times during a three hour        period before the second challenge (3 h, 2 h, 1 h, 40 min., and        10 min.).

Challenge.

Allergic conjunctivitis was achieved by a single administration on Day15 (30 minutes before the treatment regimen) and Day 18 (2 hours after40 minute treatment) with 10 μl of 5 mg/ml ovalbumin in PBS, pH 7.3-7.4to the right eyes of all rats in groups 2 through 5. Group 1 was mockchallenged with 10 μl PBS only.

On Day 19 (12 h to 24 h after challenge), rats were euthanized using anintraperitoneal injection of pentobarbital. Right eyelids and eyeballswere immediately fixed in Bouin-Hollande solution for 24 hours andembedded in paraffin wax. Fixed samples were cut vertically into 5 to 7micrometer thick sections with a microtome in two different regions—thebulbar conjunctiva and the fornix and palpebral conjunctiva. Threesections per region were selected for analysis based on the quality ofthe sectioning. The selected sections were stained withMay-Grunwald/acid Giemsa.

After staining, digital images using 200× magnifications were taken witha Leica light microscope. Total area of subconjunctival tissue wasmeasured automatically using the Leica Application Suite (LAS) software.Eosinophils were counted throughout the whole conjunctiva in each of thethree sections per sample. The density per square millimeter ofeosinophils stained with acid Giemsa was calculated for each specimen.The average cell density per eye was calculated from the results of thesix sections.

Results. Animal Body Weight.

All animals showed normal body weight variation during the study, exceptfor Group 5 (prednisolone), which showed a slight body weight lossbetween Day 15 and Day 19 (about −4%). This weight loss is commonlyobserved during chronic corticosteroid treatments. Vehicle groups 1 and2 showed a 2% and 3% weight gain, respectively, while treatment groups 3and 4 showed a 4% and 1% weight gain, respectively.

Evaluation of Eosinophil Infiltration.

Conjunctival challenge with ovalbumin in sensitized mice triggers a latephase reaction of anaphylaxis characterized by eosinophil infiltrationinto the subconjunctival tissue. Eosinophil densities are summarized inTable 7:

TABLE 7 Eosinophil density Density Inhibition of Eosinophil Treatment(cells/mm2) Infiltration vs. Vehicle 1% Laquinimod Mean 117.5 48% SD112.3 5% Laquinimod Mean 72.5 68% SD 57.6 Pred Forte ® Reference Mean23.1 90% SD 16.9 Vehicle (sterile water) positive Mean 225.4 — controlSD 188.4 Vehicle (sterile water) negative Mean 47.1 — control SD 16.0

Topical ocular challenge with ovalbumin in sensitized mice induced alate phase reaction characterized by a significant eosinophilinfiltration in to the conjunctival tissues. As shown above, topicaladministration of 1% prednisolone induced a significant decrease by 90%of the eosinophil density, with a Mann & Whitney-U test p value of0.0008. Multiple topical administrations of 1% laquinimod reducedeosinophil density by 48% in comparison with positive control; however,this could not be shown to be statistically significant. Multipletopical administrations of 5% laquinimod showed a statisticallysignificant 68% reduction in eosinophil density over the vehicle group,with a Mann & Whitney-U test p value of 0.0023.

Conclusion.

Under experimental conditions, multiple topical administrations oflaquinimod inhibited the late ocular anaphylaxis reaction in mice, witha statistically significant effect at a dose of 5%. No adverse clinicaleffect was observed in laquinimod-treated mice.

Example 3: Dose Conversion Between Species

The National Institutes of Health (NIH) provides a table of EquivalentSurface Area Dosage Conversion Factors below (Table 8) which providesconversion factors that account for surface area to weight ratiosbetween species.

TABLE 8 Equivalent Surface Area Dosage Conversion Factors To Mouse RatMonkey Dog Man 20 g 150 g 3 kg 8 kg 60 kg From Mouse 1 ½ ¼ ⅙ 1/12 Rat 21 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 6 4 1⅔ 1 ½ Man 12 7 3 2 1

In the examples 4-9 below, the administration of the composition is oncedaily. The administration can be repeated daily for a period of one,two, three or four days, up to 14 days, or longer as necessary.

Example 4: Laquinimod for Treating Uveitis

A laquinimod composition as described herein is administered to the eyeof a subject suffering from uveitis. The administration of thecomposition is effective to treat the subject suffering from uveitis.The administration of the composition is also effective to reduceintraocular inflammation in the subject. The administration of thecomposition is also effective to reduce retina tissue destruction in thesubject.

Example 5: Laquinimod for Treating Bacterial Conjunctivitis

A laquinimod composition as described herein is administered to asubject suffering from bacterial conjunctivitis. The administration ofthe composition is effective to treat the subject suffering frombacterial conjunctivitis. The administration of the composition is alsoeffective to reduce intraocular inflammation in the subject.

Example 6: Laquinimod for Treating Viral Conjunctivitis

A laquinimod composition as described herein is administered to asubject suffering from viral conjunctivitis. The administration of thecomposition is effective to treat the subject suffering from viralconjunctivitis. The administration of the composition is also effectiveto reduce intraocular inflammation in the subject.

Example 7: Laquinimod for Treating Inflammation in the Eye

A laquinimod composition as described herein is administered to asubject suffering from an inflammation of the orbital tissue, thelacrimal apparatus, the eyelid, the cornea, the retina or the opticpathway in the eye. The administration of the composition is effectiveto treat the subject suffering from the inflammation. The administrationof the composition is also effective to reduce intraocular inflammationin the subject.

Example 8: Laquinimod for Treating Allergic Conjunctivitis

A laquinimod composition as described herein is administered to asubject suffering from allergic conjunctivitis at 0.2 mg-0.5 mglaquinimod/day. The administration of the composition is effective totreat the subject suffering from allergic conjunctivitis. Theadministration of the composition is also effective to reduceintraocular inflammation in the subject. The administration of thecomposition is also effective to inhibit late ocular anaphylaxis in thesubject. The administration of the composition is also effective reduceeosinophil infiltration into the conjunctiva of the subject.

Example 9: Laquinimod for Treating OID

A laquinimod composition as described herein is administered to asubject suffering from an OID. The administration of the composition iseffective to treat the subject suffering from the OID. Theadministration of the composition is also effective to reduceintraocular inflammation in the subject.

Example 10: Comparing Ocular and Oral Administration of Laquinimod forTreating Uveitis Methods.

Laquinimod eye drops (1% and 5%) and oral laquinimod (OD) daily (QD)were administered to albino rats. The animals were dosed for 7 days once30-40% of the animals have developed the disease. Cyclosporine (PO, QD)was used as positive control.

Disease was induced as follows: Day 1, 100-μL human S-antigen (100 μg inFreud's complete adjuvant (4 mg/mL H37Ra)) injection in footpad+1 μg/100μL pertussis toxin intraperitoneal injection.

Results.

Response to treatment were assessed by clinical score based on thefollowing scale:

-   -   0—No sign of inflammation, normal iris dilatation after        instillation with a mydriatic drug.    -   1—Discrete inflammation in iris and conjunctiva.    -   2—Dilatation of iris and conjunctival vessels.    -   3—Hyperhemia in iris associated or not with the Tyndall effect        in anterior chamber.

4-7—+1 point was added if synechia, myosis, fibrin, or hypopion (celldeposit in the inferior anterior chamber) were observed.

Results are summarized in Table 9 below:

Dose % Inhibition of clinical score on Day 16 CyA 74% 1% PO Laquinimod24% 5% PO laquinimod 39% 1% Laquinimod eye drops −75% 5% Laquinimod eyedrops 31%

Results for Histological analysis is shown in Table 10 below:

Histological ocular evaluation (scale 0-7) Treatment Both Eyes/Day 19 %Inhibition Vehicle Mean 3.0 N/A (1x/day for 7 days; SD 1.6 1 mL/kg; peros) Laquinimod Mean 2.8 7.00% (1%; 1x 10 μl SD 1.5 instillation/day for7 days in both eyes) Laquinimod Mean 1.8 40.00% (5%; 1x 10 μl SD 1.7instillation/day for 7 days in both eyes) Laquinimod Mean 2.3 23.00%(1%; 1x/day for 7 SD 1.7 days; 1 mL/kg; per os) Laquinimod Mean 1.260.00% (5%; 1x/day for 7 SD 1.6 days; 1 mL/kg; per os) Cyclosporin AMean 1.3 57.00% (1x/day for 7 days; 25 mg/kg/ SD 1.7 day; per os)

REFERENCES

-   1. U.S. Pat. No. 6,077,851, issued Jun. 20, 2000 (Bjork et al).-   2. U.S. Patent Application Publication No. 2005/0192315, published    Sep. 1, 2005 (Jansson et al.).-   3. PCT International Application Publication No. WO 2005/074899,    published Aug. 18, 2005 (Jansson et al.).-   4. “Ophthalmologic Disorders” The Merck Manual, 17th ed. Mark H.    Beers, MD, Robert Berkow, MD, eds. Whitehouse Station, N.J.: Merck    Research Labs, 1999.-   5. Foster CS (2003) “Ocular Inflammatory Disease: The Importance of    Aggressive Therapy”, Highlights of the American Academy of    Ophthalmology 2003 Annual Meeting —Medscape Education.-   6. Gordon (2006) “Orbital inflammatory disease: a diagnostic and    therapeutic challenge”, Nature, 20:1196-1206.-   7. Mishra et al. (2011) “Recent Patents and Emerging Therapeutics in    the Treatment of Allergic Conjunctivitis”, Recent Pat Inflamm    Allergy Drug Discov. 2011 January; 5(1):26-36.-   8. Rothova et al. (1992) “Uveitis and systemic disease”, British    Journal of Ophthalmology, 76:137-141.-   9. Sergott (2011) “Oral MS Medication May Increase Risk Of Macular    Edema In Some Patients”, Ocular Surgery News U.S. Edition. Sep. 10,    2011.-   10. Shah et al. (1992) “Low-dose Methotrexate Therapy For Ocular    Inflammatory Disease”, Ophthalmology. 1992 September; 99(9):1419-23.-   11. The Merck Manual, Seventeenth Edition. (1999) Ed. Mark H. Beers    and Robert Berkow, Published by Merck Research Laboratories,    Whitehouse Station, N.J.-   12. “Optometric Clinical Practice Guideline—Care of the Patient with    Conjunctivitis”, American Optometric Association., 1995, 2002,    243 N. Lindbergh Blvd., St Louis, Mo. 63141-7881.

What is claimed is:
 1. A method of treating a subject suffering from anocular inflammatory disease, the method comprising periodicadministration to the subject of a therapeutically effective amount oflaquinimod or a pharmaceutically acceptable salt thereof effective totreat the subject.
 2. The method of claim 1, wherein the therapeuticallyeffective amount of laquinimod is effective to reduce a symptom of theocular inflammatory disease in the subject, induce clinical response,induce or maintain clinical remission, inhibit disease progression,inhibit a disease complication, reduce intraocular inflammation orreduce retina tissue destruction in the subject.
 3. The method of claim1 or 2, wherein the ocular inflammatory disease is uveitis, bacterialconjunctivitis, viral conjunctivitis, or an inflammation of the orbitaltissue, the lacrimal apparatus, the eyelid, the cornea, the retina orthe optic pathway.
 4. The method of claim 3, wherein the ocularinflammatory disease is conjunctivitis and the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof iseffective to reduce a symptom of conjunctivitis in the subject.
 5. Themethod of claim 3, wherein the ocular inflammatory disease is uveitisand the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduce asymptom of uveitis in the subject.
 6. The method of claim 5, wherein theuveitis is anterior uveitis, intermediate uveitis, posterior uveitis, ordiffuse uveitis.
 7. The method of claim 3, wherein the ocularinflammatory disease is an inflammation of the orbital tissue, thelacrimal apparatus, the eyelid, the cornea, the retina or the opticpathway and the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduce asymptom of the inflammation in the subject.
 8. The method of any one ofclaims 1-7, wherein the laquinimod or pharmaceutically acceptable saltthereof is administered in the form of a liquid or a gel.
 9. The methodof claim 8, wherein the concentration of laquinimod or pharmaceuticallyacceptable salt thereof in the liquid or gel 5-100 mg/ml solution. 10.The method of claim 9, wherein the concentration of laquinimod orpharmaceutically acceptable salt thereof is 10-15 mg/ml solution. 11.The method of any one of claims 1-10, wherein the therapeuticallyeffective amount of laquinimod or pharmaceutically acceptable saltthereof is 0.05-4.0 mg per administration.
 12. The method of claim 11,wherein the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is 0.05-2.0 mg peradministration.
 13. The method of claim 12, wherein the therapeuticallyeffective amount of laquinimod or pharmaceutically acceptable saltthereof is about 0.1 mg per administration.
 14. The method of claim 12,wherein the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is about 0.5 mg peradministration.
 15. The method of claim 1 or 2, wherein the ocularinflammatory disease is allergic conjunctivitis or uveitis and whereinthe therapeutically effective amount of laquinimod or pharmaceuticallyacceptable salt thereof is at least 0.2 mg/day.
 16. The method of claim15, wherein the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is effective to reduce asymptom of the allergic conjunctivitis or uveitis in the subject. 17.The method of claim 15 or 16, wherein the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof iseffective to inhibit late ocular anaphylaxis in the subject
 18. Themethod of any one of claims 15-17, wherein the therapeutically effectiveamount of laquinimod or pharmaceutically acceptable salt thereof iseffective to reduce eosinophil infiltration into the conjunctiva of thesubject.
 19. The method of claim 18, wherein the eosinophil infiltrationinto the conjunctiva is measured by eosinophil density in theconjunctiva.
 20. The method of claim 19, wherein the eosinophil densityis reduced by at least 40% as compared to a subject not administeredlaquinimod or pharmaceutically acceptable salt thereof.
 21. The methodof claim 20, wherein the eosinophil density is reduced by at least 60%as compared to a subject not administered laquinimod or pharmaceuticallyacceptable salt thereof.
 22. The method of any one of claims 15-21,wherein the laquinimod or pharmaceutically acceptable salt thereof isadministered in the form of a liquid or a gel.
 23. The method of claim22, wherein the concentration of laquinimod or pharmaceuticallyacceptable salt thereof in the liquid or gel is 20-100 mg/ml solution.24. The method of claim 23, wherein the concentration of laquinimod orpharmaceutically acceptable salt thereof is 20-50 mg/ml solution. 25.The method of any one of claims 15-24, wherein the therapeuticallyeffective amount of laquinimod or pharmaceutically acceptable saltthereof is 0.2-4.0 mg per administration.
 26. The method of claim 25,wherein the therapeutically effective amount of laquinimod orpharmaceutically acceptable salt thereof is 0.2-2.0 mg peradministration.
 27. The method of claim 26, wherein the therapeuticallyeffective amount of laquinimod or pharmaceutically acceptable saltthereof is about 0.5 mg per administration.
 28. The method of any one ofclaims 1-27, wherein the periodic administration is once per day. 29.The method of any one of claims 1-28, wherein the periodicadministration is oral administration.
 30. The method of any one ofclaims 1-29, wherein the periodic administration is ocularadministration.
 31. The method of any one of claims 1-30, wherein thepharmaceutically acceptable salt of laquinimod is laquinimod sodium. 32.The method of any one of claims 1-31, wherein the subject is a human.33. A pharmaceutical composition comprising laquinimod or apharmaceutically acceptable salt thereof for use in treating a subjectsuffering from an ocular inflammatory disease.
 34. A pharmaceuticalcomposition comprising laquinimod or a pharmaceutically acceptable saltthereof for use in treating a subject suffering from uveitis, bacterialconjunctivitis, viral conjunctivitis, or an inflammation of the orbitaltissue, the lacrimal apparatus, the eyelid, the cornea, the retina orthe optic pathway.
 35. A pharmaceutical composition for use in treatinga subject suffering from allergic conjunctivitis or uveitis comprising aunit dose of 10 μL of an aqueous pharmaceutical solution which containsin solution at least 0.2 mg laquinimod or a pharmaceutically acceptablesalt thereof.
 36. A method of treating a subject suffering from anautoimmune disease-associated ocular inflammation, the method comprisingperiodic ocular administration to the subject of a therapeuticallyeffective amount of laquinimod or a pharmaceutically acceptable saltthereof effective to treat the subject.
 37. An ocular pharmaceuticalcomposition comprising laquinimod or a pharmaceutically acceptable saltthereof for use in treating an autoimmune disease-associated ocularinflammation.